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1 Articles Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group* Summary Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR years), who after 3 months diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of mmol/l were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/l. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/l. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. *Study organisation given at end of paper Correspondence to: Prof Robert Turner, UKPDS Group, Diabetes Research Laboratories, Radcliffe Infirmary, Oxford OX2 6HE, UK Findings Over 10 years, haemoglobin A 1c (HbA 1c ) was 7 0% ( ) in the intensive group compared with 7 9% ( ) in the conventional group an 11% reduction. There was no difference in HbA 1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1 21, p=0 029) for any diabetes-related endpoint; 10% lower ( 11 to 27, p=0 34) for any diabetes-related death; and 6% lower ( 10 to 20, p=0 44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7 40, p=0 0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0 0001). The rates of major hypoglycaemic episodes per year were 0 7% with conventional treatment, 1 0% with chlorpropamide, 1 4% with glibenclamide, and 1 8% with insulin. Weight gain was significantly higher in the intensive group (mean 2 9 kg) than in the conventional group (p<0 001), and patients assigned insulin had a greater gain in weight (4 0 kg) than those assigned chlorpropamide (2 6 kg) or glibenclamide (1 7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia. Lancet 1998; 352: See Commentary page xxx Introduction Started in 1977, the UK Prospective Diabetes Study (UKPDS) was designed to establish whether, in patients with type 2 diabetes, intensive blood-glucose control reduced the risk of macrovascular or microvascular complications, and whether any particular therapy was advantageous. Most intervention studies have assessed microvascular disease: improved glucose control has delayed the THE LANCET Vol 352 September 12,

2 Figure 1: Trial profile development and progression of retinopathy, nephropathy, and neuropathy in patients with type 1 diabetes 1,2 and those with type 2 diabetes. 3 In the UK, 9% of patients with type 2 diabetes develop microvascular disease within 9 years of diagnosis, but 20% have a macrovascular complication and macrovascular disease accounts for 59% of deaths in these patients. 4 Epidemiological studies of the general population have shown an increased risk of cardiovascular disease with concentrations of fasting glucose or haemoglobin A 1c (HbA 1c ) just above the normal range. 5,6 The only previous large-scale randomised trial in type 2 diabetes, the University Group Diabetes Program (UGDP), 7 followed 1000 patients assigned different therapies for about 5 5 years (range 3 8 years) and found no evidence that improved glucose control, by any therapy, reduced the risk of cardiovascular endpoints. That study did, however, report increased risk of cardiovascular mortality in patients allocated the sulphonylurea, tolbutamide, and this unexpected finding introduced new hypotheses. 8 These hypotheses included increased myocardial damage from inhibition of ATP-K + channel opening in the presence of myocardial ischaemia 9 due to sulphonylurea binding to the cardiovascular SUR2 receptor an event that could also increase the likelihood of ventricular arrhythmia. 10 An increase in atherosclerosis with insulin treatment has also been suggested, since plasma insulin concentrations are supraphysiological. 11,12 We report the final results of our study of intensive blood-glucose control policy, with sulphonylurea or insulin therapy, compared with conventional treatment policy with diet, on the risk of microvascular and macrovascular clinical complications. We also investigated whether there was any particular benefit or risk with sulphonylurea or insulin therapy. Methods Patients Between 1977 and 1991, general practitioners in the catchment areas of the 23 participating UKPDS hospitals were asked to refer all patients with newly diagnosed diabetes aged years. Patients generally attended a UKPDS clinic within 2 weeks of referral. Patients who had a fasting plasma glucose (FPG) greater than 6 mmol/l on two mornings, 1 3 weeks apart, were eligible for the study. An FPG of 6 mmol/l was selected because this was just above the upper limit of normal for our reference range. The exclusion criteria were: ketonuria more than 3 mmol/l; serum creatinine greater than 175 µmol/l; myocardial infarction in the previous year; current angina or heart failure; more than one major vascular event; retinopathy requiring laser treatment; malignant hypertension; uncorrected endocrine disorder; occupation that precluded insulin therapy (eg, driver of heavy goods vehicle); severe concurrent illness that would limit life or require extensive systemic treatment; inadequate understanding; and unwillingness to enter the study patients were referred and 5102 were recruited (58% male). The 2514 patients excluded were similar in age, sex, and glycaemic status to those recruited. The study design and protocol amendments, which conform with the guidelines of the 838 THE LANCET Vol 352 September 12, 1998

4 Assigned therapy in 15 centres ( person-years) Assigned therapy in all 23 centres ( person-years) Conventional Chlorpropamide Glibenclamide Insulin Conventional Intensive (n=896) (n=619) (n=615) (n=911) (n=1138) (n=2729) Total person-years Actual therapy (person years) Diet alone 5495 (58%) 409 (6%) 432 (7%) 1896 (19%) 6490 (58%) 3206 (12%) Chlorpropamide alone or in combination 621 (7%) 5266 (80%) 126 (2%) 66 (1%) 743 (7%) 6372 (24%) Glibenclamide alone or in combination 1699 (18%) 483 (7%) 5467 (83%) 823 (8%) 1715 (15%) 6789 (25%) Glipizide alone or in combination 47 (0 5%) 28 (0 4%) 17 (0 3%) 58 (1%) 281 (3%) 1359 (5%) Metformin alone or in combination 1105 (12%) 900 (14%) 1319 (20%) 329 (3%) 1132 (10%) 2581 (10%) Insulin 1458 (15%) 615 (9%) 681 (10%) 7215 (74%) 1809 (16%) (38%) Table 3: Person-years of follow-up on assigned and actual therapies for first 15 and all centres Randomisation The flow of patients in the study is shown in figure 1. Patients were stratified by ideal bodyweight (overweight was >120% ideal bodyweight). 14 Non-overweight patients were randomly assigned intensive treatment with insulin (30%), intensive treatment with sulphonylurea (40%: equal proportions in the first 15 centres to chlorpropamide or glibenclamide, and in the last eight centres to chorpropamide or glipizide), or conventional treatment with diet (30%). The non-balanced randomisation was chosen so that there were sufficient patients in the two sulphonylurea groups to allow comparison between the first-generation and second-generation drugs. Overweight patients were randomly assigned treatment with the additional possibility of metformin: intensive treatment with insulin (24%), intensive treatment with sulphonylurea with equal proportions of patients on chlorpropamide and glibenclamide (32%), intensive treatment with metformin (20%), and conventional treatment with diet (24%). The 342 overweight patients who were randomly allocated metformin therapy are reported separately, as intended per protocol. 15 Randomisation was by means of centrally produced, computer-generated therapy allocations in sealed, opaque envelopes which were opened in sequence. The numerical sequence of envelopes used, the dates they were opened, and the therapies stipulated were monitored. The trial was open once patients were randomised. No placebo treatments were given. Conventional treatment policy The aim in this group was to maintain FPG below 15 mmol/l without symptoms of hyperglycaemia. Patients attended UKPDS clinics every 3 months and received dietary advice from a dietician with the aim of maintaining near-normal bodyweight. If marked hyperglycaemia or symptoms occurred, patients were secondarily randomised to treatment with sulphonylurea or insulin therapy, with the additional option of metformin in overweight patients; this was a separate stratified randomisation from the original randomisation, but with the same proportions allocated sulphonylurea and insulin. 13 If marked hyperglycaemia recurred in participants secondarily allocated sulphonylurea, metformin was added, and in those secondarily allocated metformin, glibenclamide was added. Patients with marked hyperglycaemia or symptoms on both agents were changed to insulin. Throughout, the aim of FPG below 15 mmol/l without symptoms was maintained. Clinical centres were advised by automatically generated letters when patients allocated conventional treatment received inappropriate pharmacological therapy. Intensive treatment policy The aim of intensive treatment was FPG less than 6 mmol/l and, in insulin-treated patients, pre-meal glucose concentrations of 4 7 mmol/l. These patients also continued to receive dietary advice from a dietician. The daily doses of the sulphonylureas used were: chlorpropamide mg; glibenclamide mg; and glipizide mg. Whenever glucose concentrations were above target concentrations, a letter was sent from the coordinating center with advice on necessary changes in therapy. Patients assigned insulin started on once daily ultralente insulin (Ultratard HM, Novo-Nordisk, Crawley, UK or Humulin Zn, Eli-Lilly, Basingstoke, UK) or isophane insulin. If the daily dose was more than 14 units (U) or pre-meal or bed-time home bloodglucose measurements were more than 7 mmol/l, a short-acting insulin, usually soluble (regular) insulin was added ie, basal/bolus regimen. Patients on more than 14 U insulin per day, or on short-acting insulins, were particularly encouraged to do regular home-glucose monitoring. Protocol and amendments The original protocol for the first 15 centres stipulated that patients continue their assigned treatment (diet, chlorpropamide, glibenclamide, metformin, or insulin) for as long as possible to achieve maximum exposure to each therapy alone and thus find out whether there were differences in response to each agent. Additional therapies were added to those allocated to diet, sulphonylurea, or metformin only when marked hyperglycaemia developed. For patients on sulphonylureas, metformin was added; but if marked hyperglycaemia recurred, patients were changed to insulin therapy. Metformin was used to a maximum of 2550 mg per day. When the progressive hyperglycaemia in all groups became apparent, the protocol was amended to allow the early addition of metformin when, on maximum doses of sulphonylurea, FPG was greater than 6 mmol/l in symptomless patients in the intensive group. Patients were changed to insulin therapy if marked hyperglycaemia recurred. When the last eight centres were recruited in 1988, patients allocated sulphonylurea had insulin added early, rather than metformin, when on maximum doses of sulphonylurea FPG was greater than 6 mmol/l. Embedded studies 1148 UKPDS patients were in the Hypertension in Diabetes Study (HDS). 16 This study, which started in 1987, randomly allocated hypertensive patients to a tight blood-pressure-control treatment that aimed for a blood pressure of 150/85 mm Hg or lower with either captopril or atenolol or, to a less tight bloodpressure-control treatment that aimed for a blood pressure of 180/105 mm Hg or lower but avoided the use of captopril and atenolol. The UKPDS Acarbose Study 17 started in 1994 and randomly allocated 1946 patients to additional double-blind, placebo-controlled therapy with acarbose for 3 years irrespective of their blood-glucose and blood-pressure control allocations. Clinic visits Patients attended morning clinics every 3 months or more frequently as needed to attain glycaemic control. From 1990, the routine clinic visits were every 4 months. Patients fasted from 2200 h the night before for plasma glucose and other biochemical measurements, and did not take their allocated treatment on the morning of the clinic visit. At each visit plasma glucose, blood pressure, and weight 840 THE LANCET Vol 352 September 12, 1998

5 Figure 2: Cross-sectional and 10-year cohort data for FPG, HbA 1c, weight, and fasting plasma insulin in patients on intensive or conventional treatment were measured, and therapy was adjusted if necessary. From a checklist we asked about all medications, hypoglycaemic episodes, home blood-glucose measurements, illness, time off work, admissions to hospital, general symptoms including any drug side-effects, and clinical events. Hypoglycaemic episodes were defined as minor if the patient was able to treat the symptoms unaided, or major if third-party help or medical intervention was necessary. Details of all major hypoglycaemic episodes were audited to ensure the coding was appropriate. At entry, randomisation, 6 months, 1 year, and annually thereafter a fasting blood sample was taken for measurement of HbA 1c, plasma creatinine (annually from 1989), triglyceride, total cholesterol, LDL-cholesterol, HDL-cholesterol, insulin, and insulin antibodies. Every year, urinary albumin and creatinine were measured in a random urine sample. At entry and then every 3 years all patients had a full clinical examination. At these reviews, a 12-lead electrocardiogram was recorded and Minnesota coded 13 and a posterior-anterior chest radiograph taken for measurement of cardiac diameter. Doppler blood pressure was measured in both legs and in the right arm. Visual acuity was measured with a Snellen chart until 1989 and subsequently with an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. 13 The best attainable vision was assessed with the patient s usual spectacles or with a pinhole. Direct ophthalmoscopy with pupil dilation was carried out every 3 years. Since 1982, retinal colour 30º photographs of four fields per eye (nasal, disc, macula, and temporal-to-macula fields) were taken with additional stereo photographs of the macula; poor quality photographs were repeated. Two assessors at a single centre reviewed the photographs for diabetic retinopathy; any fields with retinopathy were graded by two other assessors by a modified ETDRS final scale. 13 Neuropathy was assessed clinically by knee and ankle reflexes and by biothesiometer (Biomedical Instruments Co, Newbury, OH, USA) readings at the lateral malleolus and at the end of the big toe. 13 Autonomic neuropathy was assessed by: R-R intervals measured on electrocardiograms at expiration and inspiration on deep breathing for five cycles; change in R-R interval on standing; basal heart rate during deep breathing; lying and standing blood pressure; and, in men, self-reported erectile dysfunction. These assessments, including visual acuity, grading of photographs, and Minnesota coding, were carried out by staff from whom the allocations and actual therapies were concealed. Biochemistry Methods have been reported previously. 18 Plasma glucose analysers were monitored monthly in each clinical centre by the UKPDS Glucose Quality Assurance Scheme; the mean interlaboratory imprecision was 4% and values were THE LANCET Vol 352 September 12,

6 Figure 3: Cross-sectional and 10-year cohort data for FPG, HbA 1c, weight, and fasting plasma insulin in patients on chlorpropamide, glibenclamide, or insulin, or conventional treatment within 0 1 mmol/l of those obtained by UK External Quality Assessment Scheme. Plasma creatinine, urea, and urate were measured in the clinical chemistry laboratories at the clinical centres. Blood, plasma and urine samples were transported overnight at 4 C to the central biochemistry laboratory for all other measurements. HbA 1c was measured by high-performance liquid chromatography (Biorad Diamat Automated Glycosylated Haemoglobin Analyser, Hemel Hempstead, UK), and the normal range is %. 18 By comparison with the US National Glycohemoglobin Standardization Program, HbA 1c (UKPDS)=1 104 HbA 1c (DCCT) , (r=0 99, n=40). From 1988 urine albumin was measured by an immunoturbidimetric method (reference range mg/l). 18 Microalbuminuria has been defined for this study as a urinary albumin concentration greater than 50 mg/l due to initial storage of urine samples at 20 C between 1979 and 1988, and clinical-grade proteinuria as urinary albumin concentrations greater than 300 mg/l. 19 Insulin was measured by double-antibody radioimmunoassay (Pharmacia RIA 100 Pharmacia Upjohn, Milton Keynes, UK) with 100% cross-reaction to intact proinsulin and 25% to 32/33 split proinsulin. Clinical endpoints 21 clinical endpoints were predefined in the study protocol in and are listed later. Particular disorders were defined: myocardial infarction by WHO clinical criteria with electrocardiogram/enzyme changes or new pathological Q wave; angina by WHO clinical criteria and confirmed by a new electrocardiogram abnormality or positive exercise test; heart failure (not associated with myocardial infarction), by clinical symptoms confirmed by Kerley B lines, râles, raised jugular venous pressure, or third heart sound; major stroke by symptoms or signs for 1 month or longer; limb amputation as amputation of at least one digit; blindness in one eye by WHO criteria with Snellen-chart visual acuity of 6/60 or worse, or ETDRS logmar 1 0 or worse, for 3 months; and renal failure by dialysis or plasma creatinine greater than 250 µmol/l not 842 THE LANCET Vol 352 September 12, 1998

7 Figure 4: Proportion of patients with aggregate and single endpoints by intensive and conventional treatment and relative risks related to any acute intercurrent illness. The clinical decision for photocoagulation or cataract extraction was made by ophthalmologists independent of the trial. Aggregate endpoints were defined by the Data-Monitoring and Ethics Committee in 1981 as time to the first occurrence of: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. These aggregates were used to assess the difference between conventional and intensive treatment. To investigate differences among chlorpropamide, insulin, and glibenclamide, four additional clinical-endpoint aggregates were used: myocardial infarction (fatal and non-fatal) and sudden death; stroke (fatal and non-fatal); amputation or death due to peripheral vascular disease; and microvascular complications (retinopathy requiring photocoagulation, vitreous haemorrhage, and or fatal or non-fatal renal failure). Surrogate endpoints Subclinical, surrogate variables were assessed every 3 years. The criteria were: for neuropathy loss of both ankle or both knee reflexes or mean biothesiometer reading from both toes 25 V or greater; for autonomic neuropathy R-R interval less than the age-adjusted normal range (a ratio <1 03 of the longest R-R interval at approximately beat 30 to the shortest at approximately beat 15); for orthostatic hypotension systolic fall of 30 mm Hg or more, or diastolic fall of 10 mm Hg or more; and for impotence no ejaculation or erection. Retinopathy was defined as one microaneurysm or more in one eye or worse retinopathy, and progression of retinopathy as a two-step change in grade. Poor visual acuity was: logmar more than 0 3 (unable to drive a car), more than 0 7 (US definition of blindness), and logmar 1 0 or greater (WHO definition of blindness). Deterioration of vision was defined as a three-line deterioration in reading an ETDRS chart. Ischaemic heart disease by Minnesota coding was either WHO grade 1 (possible coronary heart disease) or grade 2 (probable coronary heart disease). Left-ventricular hypertrophy was a cardiothoracic ratio 0 5 or greater. The study closed on Sept 30, All available information for each endpoint, such as admission notes, operation records, death certificates, and necropsy reports, were gathered. The file, with no reference to assigned or actual therapy, was reviewed independently by two physicians who assigned appropriate International Classification of Disease 9 codes. 20 Any disagreements between the two assessors were discussed and the evidence reviewed; if agreement was not possible the file was submitted to two different assessors for final arbitration. Statistical analysis When the UKPDS started in the late 1970s, it was thought that improved blood-glucose control might reduce the incidence of diabetes-related endpoints by 40%. This seemed reasonable since the risk of cardiovascular events in patients with diabetes is at least twice that of people with normal glucose tolerance and microvascular complications do not occur in the normoglycaemic population. The first three aggregate endpoints were defined and, for death and major cardiovascular events (the stopping criteria), the original power calculation to find a 40% difference between the intensive and conventional groups was a sample size of 3600 with 81% power at the 1% level of significance. However, by 1987 no risk reduction was seen in any of these aggregates and it became obvious a 40% advantage was unlikely to be obtained. The publication of other intervention studies of chronic diseases in the mid 1980s suggested that a more realistic goal would be a difference of 15%. Accordingly, the study was extended to include randomisation of 3867 patients with a median time from randomisation of 11 years to the end of the study in In 1992, at the 1% level of significance, the power for any diabetes-related endpoint and for diabetesrelated death was calculated as 81% and 23%, respectively. There was the same proportion of patients in the THE LANCET Vol 352 September 12,

8 Figure 5: Proportion of patients with aggregate and single endpoints by individual intensive treatment and conventional treatment and relative risks Key as for figure 4. non-overweight and overweight stratifications assigned intensive and conventional treatment, and, within the intensive group, sulphonylurea or insulin treatment, and thus the non-overweight and overweight patients are analysed together. The 3867 patients from all 23 centres were included in the analyses of conventional and intensive treatment. The analysis among chlorpropamide, glibenclamide, or insulin in the intensive group used only 3041 patients from the first 15 centres where patients had remained for longer periods on monotherapy until marked hyperglycaemia occurred. Intention-to-treat analysis was used to compare outcomes between the intensive and conventional treatment groups and between the patients on conventional treatment and those on each of the intensive treatment agents. All analyses of significance were two-sided (2p). Life-table analyses were done with log-rank tests. Hazard ratios, used to estimate relative risks, were obtained from Cox proportionalhazards models. In the text, the relative risks are quoted in terms of risk reduction. For the clinical endpoint aggregates, 95% CI are quoted. For single endpoints and surrogate variables 99% CI are given to make allowance for potential type I errors. Mean (SD), geometric mean (1SD interval), or median (IQR) have been quoted for the biometric and biochemical variables, with Wilcoxon, t test, or χ 2 for comparison tests. Risk reductions for categorical variables were derived from relative risks obtained from frequency tables. Survival-function estimates were calculated by the product-limit (Kaplan-Meier) method. Yearly averaged data for weight and FPG were calculated as the median of three consecutive visits for each patient ie, the annual visit, and the 3 month visit before and after this. HbA 1c data were from the annual assessment but overall values for HbA 1c during a period were the median for each patient for each allocation. Glucose control and HbA 1c were assessed both cross-sectionally and in the cohort with 10 years follow-up. Urine albumin was assessed in mg/l with no adjustment for urine creatinine concentration. 21 Data for albuminuria at the triennial visit were the median of that year and the years before and after. Hypoglycaemic episodes in each year were analysed both by intention to treat and by actual therapy. Safety The Data-monitoring and Ethics Committee reviewed the endpoint analyses every 6 months to decide whether to stop or modify the study according to predetermined guidelines. These 844 THE LANCET Vol 352 September 12, 1998

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